RFX5调控原钙粘蛋白α基因簇的表达

doi:10.16288/j.yczz.20-184

遗传 ›› 2020, Vol. 42 ›› Issue (8): 760-774.doi: 10.16288/j.yczz.20-184

RFX5调控原钙粘蛋白α基因簇的表达

王娜, 甲芝莲, 吴强()

上海交通大学系统生物医学研究院比较生物医学研究中心,系统生物医学教育部重点实验室,上海 200240

收稿日期:2020-06-19 修回日期:2020-07-08 出版日期:2020-08-20 发布日期:2020-07-29
通讯作者: 吴强 E-mail:qwu123@gmail.com
作者简介:王娜,在读硕士研究生,专业方向：生物学。E-mail: 1191593019@qq.com
基金资助:
国家自然科学基金项目资助编号(91640118);国家自然科学基金项目资助编号(31630039)

RFX5 regulates gene expression of the Pcdhα cluster

Wang Na, Jia Zhilian, Wu Qiang()

Center for Comparative Biomedicine, Key laboratory of Systems Biomedicine (Ministry of Education), Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China

Received:2020-06-19 Revised:2020-07-08 Online:2020-08-20 Published:2020-07-29
Contact: Wu Qiang E-mail:qwu123@gmail.com
Supported by:
Supported by the National Natural Science Foundation of China Nos(91640118);Supported by the National Natural Science Foundation of China Nos(31630039)

摘要/Abstract

摘要：

基因的表达调控与基因组在细胞核内的三维空间架构相辅相成,原钙粘蛋白(protocadherin, Pcdh)基因簇在大脑发育中起到关键作用,可以作为研究基因表达调控机制的模式基因。转录因子RFX5 (regulatory factor x 5)是翼螺旋家族(winged HLH family)的成员,其蛋白由寡聚化结构域、DNA结合域、螺旋结构域和激活域组成,在调控免疫系统的主要组织相容性复合物II类(major histocompatibility complex class II, MHC II)的表达中起着至关重要的作用。本研究发现RFX5与CTCF在全基因组上结合的位点有部分重叠,利用CRISPR/Cas9 DNA大片段编辑技术,构建了RFX5基因缺失的HEC-1-B细胞系。通过RNA-seq实验,发现RFX5敲除能够显著升高Pcdhα6、Pcdhα12、Pcdhαc2的表达水平。通过ChIP-nexus实验,发现敲除RFX5导致染色质架构蛋白CTCF和cohesin在原钙粘蛋白α基因簇处的结合增加。最后,染色质构象捕获QHR-4C实验发现Pcdhα6、Pcdhα12启动子与远端增强子HS5-1的染色质远距离相互作用增强。上述研究表明RFX5蛋白可能通过调控染色质高级结构影响原钙粘蛋白α基因簇的表达,为未来进一步探索RFX5的功能提供了参考。

关键词: RFX5, Pcdh, CTCF, cohesin, CRISPR/Cas9

Abstract:

Gene expression and three-dimensional (3D) genome organization are thought to be closely related. The protocadherin (Pcdh) clusters are central for neuronal self-avoidance in brain development and have been used as model genes to explore the role of 3D genome structures in gene regulation. Transcription factor RFX5 (regulatory factor x 5) is a member of the winged-helix subfamily of the helix-turn-helix superfamily proteins. The RFX5 protein contains four domains: oligomerization, DNA-binding, helical, and transactivation domains. RFX5 plays an important role in regulating expression of the major histocompatibility complex class II (MHC II) gene complex. Here we report a role of RFX5 in the regulation of clustered Pcdh genes. We first knocked out the RFX5 gene by using CRISPR/Cas9 DNA-fragment editing in HEC-1-B cell line. By RNA-seq experiments, we found that RFX5 deletion results in a significant increase of expression levels of the Pcdhα6, Pcdhα12 and Pcdhαc2 genes. By ChIP-nexus experiments, we found that RFX5 deletion leads to the increased binding of CTCF and RAD21 in the Pcdhα cluster. Finally, through quantitative high-resolution chromosome conformation capture copy (QHR-4C) experiments, we found that RFX5 deletion results in a significant increase of long-distance chromatin interactions between the HS5-1 enhancer and its target promoters in the Pcdhα cluster. In conclusion, RFX5 regulates gene expression of the Pcdhα cluster through higher-order chromatin structure.

Key words: RFX5, Pcdh, CTCF, cohesin, CRISPR/Cas9

王娜, 甲芝莲, 吴强. RFX5调控原钙粘蛋白α基因簇的表达[J]. 遗传, 2020, 42(8): 760-774.

Wang Na, Jia Zhilian, Wu Qiang. RFX5 regulates gene expression of the Pcdhα cluster[J]. Hereditas(Beijing), 2020, 42(8): 760-774.

图/表 6

表1

引物序列"

类型	引物名称	序列(5′→3′)
PCR	F1	GGGAAGTCGTGGCGAGATTA
	F2	GTGCCCTGAAAGTGGCTACA
	R1	CTGGGTGACTCAGCTGTCTG
	R2	GCTGGAGGTCACACACAAGA
	R3	AGAGTAGCCTGGTGTTAGCG
sgRNA	sgRNA1F	ACCGACCCTTCTTCAGAGGCTCCG
	sgRNA1R	AAACCGGAGCCTCTGAAGAAGGGT
	sgRNA2F	ACCGAAGCAACACCCCCATGATAC
	sgRNA2R	AAACGTATCATGGGGGTGTTGCTT
Index	P5-HS5-1-F2	AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTGTTTTGGCGGCGACAAATTCG
	P5-α12-F3	AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTAGTCCAATCATTCACGGAATAGGATC
	P7-index-1	CAAGCAGAAGACGGCATACGAGATCGAGTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-2	CAAGCAGAAGACGGCATACGAGATTCTCCGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-3	CAAGCAGAAGACGGCATACGAGATAATGAGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-4	CAAGCAGAAGACGGCATACGAGATGGAATCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-5	CAAGCAGAAGACGGCATACGAGATAGCTTCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-6	CAAGCAGAAGACGGCATACGAGATGCGCATGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-7	CAAGCAGAAGACGGCATACGAGATGCGCGAGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-8	CAAGCAGAAGACGGCATACGAGATAGAGTACTGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-9	CAAGCAGAAGACGGCATACGAGATGCTCCGTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-10	CAAGCAGAAGACGGCATACGAGATCATGAGAGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-11	CAAGCAGAAGACGGCATACGAGATTGAATCGCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-12	CAAGCAGAAGACGGCATACGAGATGTCGCGTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-13	CAAGCAGAAGACGGCATACGAGATCCGCATGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-14	CAAGCAGAAGACGGCATACGAGATCCACAATCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-15	CAAGCAGAAGACGGCATACGAGATTTCATCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-16	CAAGCAGAAGACGGCATACGAGATTAGAGTGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-17	CAAGCAGAAGACGGCATACGAGATTAACTCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-18	CAAGCAGAAGACGGCATACGAGATTATACGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-19	CAAGCAGAAGACGGCATACGAGATGAGTCAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-20	CAAGCAGAAGACGGCATACGAGATGACATAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-21	CAAGCAGAAGACGGCATACGAGATGTATTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-22	CAAGCAGAAGACGGCATACGAGATGACACAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-23	CAAGCAGAAGACGGCATACGAGATGCGATAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-24	CAAGCAGAAGACGGCATACGAGATCTCTATGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT
	P7-index-25	CAAGCAGAAGACGGCATACGAGATTACGCAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT

表1

图1

图2

图3

图4

图5

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RFX5调控原钙粘蛋白α基因簇的表达

RFX5 regulates gene expression of the Pcdhα cluster

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